Certain chemical entities, compositions, and methods

ABSTRACT

Chemical entities that are novel compounds, pharmaceutical compositions and methods of treatment of cancer are described.

This application claims the benefit of U.S. Patent Application No.61/438,945, filed Feb. 2, 2011, which is hereby incorporated byreference.

Provided are certain chemical entities and compositions thereof that maybe useful in the treatment of cancer.

Cancer can be viewed as a breakdown in the communication between tumorcells and their environment, including their normal neighboring cells.Signals, both growth-stimulatory and growth-inhibitory, are routinelyexchanged between cells within a tissue. Normally, cells do not dividein the absence of stimulatory signals, and likewise, will cease dividingin the presence of inhibitory signals. In a cancerous, or neoplasticstate, a cell acquires the ability to “override” these signals and toproliferate under conditions in which normal cells would not grow.

Cardiotonic steroids like digoxin and digitoxin are a class of naturallyderived compounds that bind to and inhibit Na⁺/K⁺-ATPase (sodium pump).Members of this family have been used for the treatment of heart failureand arrhythmia for many years. Recent findings have revealed that thesecompounds may be involved in the regulation of several importantcellular processes. Several cardiotonic steroids such as digitoxin andoleandrin have shown inhibitory effect on the growth of human tumorcells.

Provided is at least one chemical entity chosen from compounds ofFormula I

and pharmaceutically acceptable salts thereof, wherein

R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ are independently chosen fromhydrogen, hydroxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substitutedheterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionallysubstituted acyloxy, optionally substituted alkoxycarbonyloxy, andoptionally substituted amino; or

R₁ and R₂, or R₅ and R₆, or R₇ and R₈, or R₉ and R₁₀, or R₁₁ and R₁₂mutually independently, together in each case denote an oxo group (═O);

R₄ is hydroxy, or R₄ and R₅ may optionally be joined together with anyintervening atoms to form an optionally substituted heterocycloalkylring;

R₇ is chosen from hydrogen, hydroxy, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted heterocycloalkyloxy, optionally substitutedaminocarbonyloxy, optionally substituted acyloxy, optionally substitutedalkoxycarbonyloxy, and optionally substituted amino;

R₈ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkenyl, and optionallysubstituted alkynyl;

R₁₃ is chosen from hydrogen, optionally substituted alkyl, and formyl;

Z is chosen from OR₁₄ and NR₁₅R₁₆; wherein

R₁₄ is chosen from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

R₁₅ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R₁₆ is chosen from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

or R₁₅ and R₁₆ may optionally be joined together with any interveningatoms to form an optionally substituted heterocycloalkyl ring;

W₁ is chosen from the following moieties:

wherein Y is chosen from O and NR₁₈;

R₁₇ is chosen from cyano, halo, hydroxy, azido, nitro, carboxy,sulfinyl, sulfanyl, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, optionallysubstituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryloxy, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, optionallysubstituted amino, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted aminocarbonyl, optionallysubstituted aminosulfonyl, optionally substituted carbaminodoyl, andoptionally substituted alkynyl;

R₁₈ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;

W₂ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkenyl, and optionallysubstituted alkynyl;

m is selected from 0, 1, 2, and 3;

n is selected from 0 and 1, and

the dotted line represents a single bond or a double bond;

provided that when R₄ is OH, R₁₃ is methyl, W₁ is

(2-oxo-2H-pyran-5-yl), and R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, andW₂ are hydrogen then R₁₂ is not hydrogen.

Also provided is a pharmaceutical composition comprising apharmaceutically acceptable carrier and at least one chemical entitydescribed herein.

Also provided is a packaged pharmaceutical composition comprising apharmaceutical composition described herein and instructions for usingthe composition to treat a subject suffering from cancer.

Also provided is a method of treating cancer in a subject whichcomprises administering to a subject in need thereof a therapeuticallyeffective amount of at least one chemical entity described herein.

As used herein, the following words and phrases are generally intendedto have the meanings as set forth below, except to the extent that thecontext in which they are used indicates otherwise.

The following abbreviations and terms have the indicated meaningsthroughout:

-   AcOH=acetic acid-   Boc=tert-butoxycarbonyl-   c-=cyclo-   DCC=dicyclohexylcarbodiimide-   DCM=dichloromethane-   DIEA=N,N-diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   eq=equivalent(s)-   Et=ethyl-   EtOAc or EA=ethyl acetate-   EtOH=ethanol-   g=gram-   h or hr=hour-   HBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt=hydroxybenzotriazole-   HPLC=high pressure liquid chromatography-   i-=iso-   kg or Kg=kilogram-   L or l=liter-   LC/MS=LCMS=liquid chromatography-mass spectrometry-   LRMS=low resolution mass spectrometry-   m/z=mass-to-charge ratio-   Me=methyl-   MeOH=methanol-   mg=milligram-   min=minute-   mL=milliliter-   mmol=millimole-   n-=normal-   NaOAc=sodium acetate-   PE=petroleum ether-   Ph=phenyl-   Prep=preparative-   quant.=quantitative-   RP-HPLC=reverse phase-high pressure liquid chromatography-   rt or RT=room temperature-   s-=sec-=secondary-   t-=tert-=tertiary-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   UV=ultraviolet

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence.

As used herein, a dash (“-”) that is not between two letters or symbolsis used to indicate a point of attachment for a substituent. Forexample, —CONH₂ is attached through the carbon atom.

As used herein, “optional” or “optionally” is meant that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances wherein the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted alkyl” encompasses both “alkyl” and “substitutedalkyl” as defined below. It will be understood by those skilled in theart, with respect to any group containing one or more substituents, thatsuch groups are not intended to introduce any substitution orsubstitution patterns that are sterically impractical, syntheticallynon-feasible and/or inherently unstable.

As used herein, “alkyl” refers to straight chain and branched chainhaving the indicated number of carbon atoms, usually from 1 to 20 carbonatoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. Forexample C₁-C₆ alkyl encompasses both straight and branched chain alkylof from 1 to 6 carbon atoms. When an alkyl residue having a specificnumber of carbons is named, all branched and straight chain versionshaving that number of carbons are intended to be encompassed; thus, forexample, “butyl” is meant to include n-butyl, sec-butyl, isobutyl andt-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refersto alkyl groups having one to six carbons. Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, and the like. Alkylene is a subset of alkyl,referring to the same residues as alkyl, but having two points ofattachment. Alkylene groups will usually have from 2 to 20 carbon atoms,for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. Forexample, C₀ alkylene indicates a covalent bond and C_(r) alkylene is amethylene group.

As used herein, “alkenyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon double bondderived by the removal of one molecule of hydrogen from adjacent carbonatoms of the parent alkyl. The group may be in either the cis or transconfiguration about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl;and the like. In certain embodiments, an alkenyl group has from 2 to 20carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Loweralkenyl” refers to alkenyl groups having two to six carbons.

As used herein, “alkynyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon triple bondderived by the removal of two molecules of hydrogen from adjacent carbonatoms of the parent alkyl. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl;butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and thelike. In certain embodiments, an alkynyl group has from 2 to 20 carbonatoms and in other embodiments, from 3 to 6 carbon atoms. “Loweralkynyl” refers to alkynyl groups having two to six carbons.

As used herein, “cycloalkyl” refers to a non-aromatic carbocyclic ring,usually having from 3 to 8 ring carbon atoms. The ring may be saturatedor have one or more carbon-carbon double bonds. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groupssuch as norbornane.

As used herein, “alkoxy” refers to an alkyl group of the indicatednumber of carbon atoms attached through an oxygen bridge such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like.Alkoxy groups will usually have from 1 to 7 carbon atoms attachedthrough the oxygen bridge. “Lower alkoxy” refers to alkoxy groups havingone to six carbons.

As used herein, “acyl” refers to the groups H—C(O)—; (alkyl)-C(O)—;(cycloalkyl)-C(O)—; (aryl)-C(O)—; (heteroaryl)-C(O)—; and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein alkyl,cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as describedherein. Acyl groups have the indicated number of carbon atoms, with thecarbon of the keto group being included in the numbered carbon atoms.For example a C₂ acyl group is an acetyl group having the formulaCH₃(C═O)—.

As used herein, “formyl” refers to the group —C(O)H.

As used herein, “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker.

As used herein, “azido” refers to the group —N₃.

As used herein, “amino” refers to the group —NH₂.

As used herein, “mono- and di-(alkyl)amino” refers to secondary andtertiary alkyl amino groups, wherein the alkyl groups are as definedabove and have the indicated number of carbon atoms. The point ofattachment of the alkylamino group is on the nitrogen. Examples of mono-and di-alkylamino groups include ethylamino, dimethylamino, andmethyl-propyl-amino.

As used herein, “aminocarbonyl” refers to the group —CONR^(b)R^(c),where

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl,optionally substituted alkoxy; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c) taken together with the nitrogen to which they arebound, form an optionally substituted 5- to 8-memberednitrogen-containing heterocycloalkyl which optionally includes 1 or 2additional heteroatoms chosen from O, N, and S in the heterocycloalkylring;

where each substituted group is independently substituted with one ormore substituents independently chosen from C₁-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl,—OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl,halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl,heterocycloalkyl, or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “aryl” refers to: 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene.

For example, aryl includes 6-membered carbocyclic aromatic rings fusedto a 5- to 7-membered heterocycloalkyl ring containing 1 or moreheteroatoms chosen from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the point of attachment may be at the carbocyclic aromatic ring or theheterocycloalkyl ring. Bivalent radicals formed from substituted benzenederivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. Bivalent radicals derived from univalentpolycyclic hydrocarbon radicals whose names end in “-yl” by removal ofone hydrogen atom from the carbon atom with the free valence are namedby adding “-idene” to the name of the corresponding univalent radical,e.g. a naphthyl group with two points of attachment is termednaphthylidene. Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with a heterocycloalkyl aromaticring, the resulting ring system is heteroaryl, not aryl, as definedherein.

As used herein, “aryloxy” refers to the group —O-aryl.

As used herein, “aralkyl” refers to the group -alkyl-aryl.

As used herein, “carbamimidoyl” refers to the group —C(═NH)—NH₂.

As used herein, “substituted carbamimidoyl” refers to the group—C(═NR^(e))—NR^(f)R^(g) where

R^(e) is chosen from hydrogen, cyano, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocycloalkyl; and

R^(f) and R^(g) are independently chosen from hydrogen optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl,

provided that at least one of R^(e), R^(f), and R^(g) is not hydrogenand wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(a) is chosen from optionally substituted C1-C6 alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C1-C6 alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C1-C4 alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, orheteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C_(j)—C₄alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO2(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂ NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “halo” refers to fluoro, chloro, bromo, and iodo, andthe term “halogen” includes fluorine, chlorine, bromine, and iodine.

As used herein, “haloalkyl” refers to alkyl as defined above having thespecified number of carbon atoms, substituted with 1 or more halogenatoms, up to the maximum allowable number of halogen atoms. Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

As used herein, “heteroaryl” refers to:

5- to 7-membered aromatic, monocyclic rings containing one or more, forexample, from 1 to 4, or in certain embodiments, from 1 to 3,heteroatoms chosen from N, O, and S, with the remaining ring atoms beingcarbon;

bicyclic heterocycloalkyl rings containing one or more, for example,from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosenfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring; and

tricyclic heterocycloalkyl rings containing one or more, for example,from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms chosenfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl,aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkylring. For such fused, bicyclic heteroaryl ring systems wherein only oneof the rings contains one or more heteroatoms, the point of attachmentmay be at either ring. When the total number of S and O atoms in theheteroaryl group exceeds 1, those heteroatoms are not adjacent to oneanother. In certain embodiments, the total number of S and O atoms inthe heteroaryl group is not more than 2. In certain embodiments, thetotal number of S and O atoms in the aromatic heterocycle is not morethan 1. Examples of heteroaryl groups include, but are not limited to,(as numbered from the linkage position assigned priority 1), 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl,oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl,benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl,pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinolinyl. Bivalent radicals derived fromunivalent heteroaryl radicals whose names end in “-yl” by removal of onehydrogen atom from the atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g. apyridyl group with two points of attachment is a pyridylidene.Heteroaryl does not encompass or overlap with aryl, cycloalkyl, orheterocycloalkyl, as defined herein

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

As used herein, “heterocycloalkyl” refers to a single, non-aromaticring, usually with 3 to 8 ring atoms, containing at least 2 carbon atomsin addition to 1-3 heteroatoms independently chosen from oxygen, sulfur,and nitrogen, as well as combinations comprising at least one of theforegoing heteroatoms. The ring may be saturated or have one or morecarbon-carbon double bonds. Suitable heterocycloalkyl groups include,for example (as numbered from the linkage position assigned priority 1),2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl,3-piperidyl, 4-piperidyl, and 2,5-piperizinyl. Morpholinyl groups arealso contemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo (═O) oroxide (—O⁻) substituents, such as piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and1,1-dioxo-1-thiomorpholinyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 8 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently chosen fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 8 ring atoms, optionally contains 1-3 heteroatoms independentlychosen from oxygen, sulfur, and nitrogen and is not aromatic.

As used herein, “sulfanyl” refers to the groups: —S-(optionallysubstituted (C₁-C₆)alkyl), —S-(optionally substituted aryl),—S-(optionally substituted heteroaryl), and —S-(optionally substitutedheterocycloalkyl). Hence, sulfanyl includes the group C₁-C₆alkylsulfanyl.

As used herein, “sulfinyl” refers to the groups: —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-optionally substituted aryl),—S(O)-optionally substituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

As used herein, “sulfonyl” refers to the groups: —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-optionally substituted heteroaryl), —S(O₂)-(optionallysubstituted heterocycloalkyl), and —S(O₂)-(optionally substitutedamino).

As used herein, “substituted” refers to any one or more hydrogens on thedesignated atom or group is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valence is notexceeded. When a substituent is oxo (i.e. ═O) then 2 hydrogens on theatom are replaced. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates. A stable compound or stable structure ismeant to imply a compound that is sufficiently robust to surviveisolation from a reaction mixture, and subsequent formulation as anagent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

As used herein, the terms “substituted” alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, unless otherwise expressly defined,refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, azido,nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)), where

R^(a) is chosen from optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;R^(b) is chosen from hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂,—C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano,nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),—CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

As used herein, “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfonyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e. —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)), whereR^(a) is chosen from optionally substituted C₁-C₆ alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄—CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

In some embodiments, a substituted alkoxy group is “polyalkoxy” or—O-(optionally substituted alkylene)-(optionally substituted alkoxy),and includes groups such as —OCH₂CH₂OCH₃, and residues of glycol etherssuch as polyethyleneglycol, and —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of 2-20, such as 2-10, and for example, 2-5. Another substitutedalkoxy group is hydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is an integerof 1-10, such as 1-4.

As used herein, “substituted alkoxycarbonyl” refers to the group(substituted alkyl)-O—C(O)— wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedrefers to alkyl wherein one or more (such as up to 5, for example, up to3) hydrogen atoms are replaced by a substituent independently chosenfrom

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(c) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(e) wherein R^(d) is chosen from hydroxyl, formyl, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted acyl, optionally substitutedcarbamimidoyl, aminocarbonyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, andwherein R^(e) is chosen from optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted heterocycloalkyl, andwherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl); and

wherein optionally substituted acyl, optionally substitutedalkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition,compounds include Z- and E-forms (or cis- and trans-forms) of compoundswith carbon-carbon double bonds. Where compounds described herein existin various tautomeric forms, the term “compound” is intended to includeall tautomeric forms of the compound.

Compounds of Formula I also include crystalline and amorphous forms ofthose compounds, including, for example, polymorphs, pseudopolymorphs,solvates (including hydrates), unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof. “Crystalline form,” “polymorph,”and “novel form” may be used interchangeably herein, and are meant toinclude all crystalline and amorphous forms of the compound, including,for example, polymorphs, pseudopolymorphs, solvates (includinghydrates), unsolvated polymorphs (including anhydrates), conformationalpolymorphs, and amorphous forms, as well as mixtures thereof, unless aparticular crystalline or amorphous form is referred to. Similarly,“pharmaceutically acceptable salts of compounds of Formula I alsoinclude crystalline and amorphous forms of those compounds, including,for example, polymorphs, pseudopolymorphs, solvates (includinghydrates), unsolvated polymorphs (including anhydrates), conformationalpolymorphs, and amorphous forms of the pharmaceutically acceptablesalts, as well as mixtures thereof.

A “solvate” is formed by the interaction of a solvent and a compound.The term “compound” is intended to include solvates of compounds.Similarly, “pharmaceutically acceptable salts” includes solvates ofpharmaceutically acceptable salts. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

Compounds of Formula I also include other pharmaceutically acceptableforms of the recited compounds, including chelates, non-covalentcomplexes, prodrugs, and mixtures thereof.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “pharmaceutically acceptable salts”includes chelates of pharmaceutically acceptable salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound”. Similarly, “pharmaceuticallyacceptable salts” includes “non-covalent complexes” of pharmaceuticallyacceptable salts.

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry.

“Hydrogen bond acceptor” refers to a group comprising an oxygen ornitrogen, such as an oxygen or nitrogen that is sp²-hybridized, an etheroxygen, or the oxygen of a sulfoxide or N-oxide.

The term “hydrogen bond donor” refers to an oxygen, nitrogen, orheteroaromatic carbon that bears a hydrogen group containing a ringnitrogen or a heteroaryl group containing a ring nitrogen.

The compounds disclosed herein can be used in different enrichedisotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or¹⁴C. In one particular embodiment, the compound is deuterated at leastone position. Such deuterated forms can be made by the proceduredescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described inU.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve theefficacy and increase the duration of action of drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

“Prodrugs” described herein include any compound that becomes a compoundof Formula I when administered to a subject, e.g., upon metabolicprocessing of the prodrug. Similarly, “pharmaceutically acceptablesalts” includes “prodrugs” of pharmaceutically acceptable salts.Examples of prodrugs include derivatives of functional groups, such as acarboxylic acid group, in the compounds of Formula I. Exemplary prodrugsof a carboxylic acid group include, but are not limited to, carboxylicacid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters,and aryloxyalkyl esters. Other exemplary prodrugs include lower alkylesters such as ethyl ester, acyloxyalkyl esters such aspivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

Other exemplary prodrugs include amides of carboxylic acids. Exemplaryamide prodrugs include metabolically labile amides that are formed, forexample, with an amine and a carboxylic acid. Exemplary amines includeNH₂, primary, and secondary amines such as NHR^(x), and NR^(x)R^(y),wherein R^(x) is hydrogen, (C₁-C₁₈)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, (C₆-C₁₄)-aryl which is unsubstitutedor substituted by a residue (C₁-C₂)-alkyl, (C₁-C₂)-alkoxy, fluoro, orchloro; heteroaryl-, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- where aryl isunsubstituted or substituted by a residue (C₁-C₂)-alkyl, (C₁-C₂)-alkoxy,fluoro, or chloro; or heteroaryl-(C₁-C₄)-alkyl- and in which R^(y) hasthe meanings indicated for R^(x) with the exception of hydrogen orwherein R^(x) and R^(y), together with the nitrogen to which they arebound, form an optionally substituted 4- to 8-membered heterocycloalkylring which optionally includes one or two additional heteroatoms chosenfrom nitrogen, oxygen, and sulfur. A discussion of prodrugs is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, and in Design of Prodrugs, ed. H.Bundgaard, Elsevier, 1985.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules.

As used herein, “modulation” refers to a change in activity as a director indirect response to the presence of a chemical entity as describedherein, relative to the activity of in the absence of the chemicalentity. The change may be an increase in activity or a decrease inactivity, and may be due to the direct interaction of the compound withthe a target or due to the interaction of the compound with one or moreother factors that in turn affect the target's activity. For example,the presence of the chemical entity may, for example, increase ordecrease the target activity by directly binding to the target, bycausing (directly or indirectly) another factor to increase or decreasethe target activity, or by (directly or indirectly) increasing ordecreasing the amount of target present in the cell or organism.

As used herein, “active agent” is used to indicate a chemical entitywhich has biological activity. In certain embodiments, an “active agent”is a compound having pharmaceutical utility. For example an active agentmay be an anti-cancer therapeutic.

As used herein, “significant” refers to any detectable change that isstatistically significant in a standard parametric test of statisticalsignificance such as Student's T-test, where p<0.05.

As used herein, a “pharmaceutically acceptable” component is one that issuitable for use with humans and/or animals without undue adverse sideeffects (such as toxicity, irritation, and allergic response)commensurate with a reasonable benefit/risk ratio.

As used herein, “therapeutically effective amount” of a chemical entitydescribed herein refers to an amount effective, when administered to ahuman or non-human subject, to provide a therapeutic benefit such asamelioration of symptoms, slowing of disease progression, or preventionof disease.

“Treating” or “treatment” encompasses administration of at least onecompound of Formula I, or a pharmaceutically acceptable salt thereof, toa mammalian subject, particularly a human subject, in need of such anadministration and includes (i) arresting the development of clinicalsymptoms of the disease, such as cancer, (ii) bringing about aregression in the clinical symptoms of the disease, such as cancer,and/or (iii) prophylactic treatment for preventing the onset of thedisease, such as cancer.

As used herein, “cancer” refers to all types of cancer or neoplasm ormalignant tumors found in mammals, including carcinomas and sarcomas.Examples of cancer are cancer of the brain, breast, cervix, colon, head& neck, kidney, lung, non-small cell lung, melanoma, mesothelioma,ovary, sarcoma, stomach, uterus and Medulloblastoma.

As used herein, “subject” refers to a mammal that has been or will bethe object of treatment, observation or experiment. The methodsdescribed herein can be useful in both human therapy and veterinaryapplications. In some embodiments, the subject is a human.

The term “mammal” is intended to have its standard meaning, andencompasses humans, dogs, cats, sheep, and cows, for example.

Provided is at least one chemical entity chosen from compounds ofFormula I

and pharmaceutically acceptable salts thereof, wherein

R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ are independently chosen fromhydrogen, hydroxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substitutedheterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionallysubstituted acyloxy, optionally substituted alkoxycarbonyloxy, andoptionally substituted amino; or

R₁ and R₂, or R₅ and R₆, or R₇ and R₈, or R₉ and R₁₀, or R₁₁ and R₁₂mutually independently, together in each case denote an oxo group (═O);

R₄ is hydroxy, or R₄ and R₅ may optionally be joined together with anyintervening atoms to form an optionally substituted heterocycloalkylring;

R₇ is chosen from hydrogen, hydroxy, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted heteroaryloxy,optionally substituted heterocycloalkyloxy, optionally substitutedaminocarbonyloxy, optionally substituted acyloxy, optionally substitutedalkoxycarbonyloxy, and optionally substituted amino;

R₈ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkenyl, and optionallysubstituted alkynyl;

R₁₃ is chosen from hydrogen, optionally substituted alkyl, and formyl;

Z is chosen from OR₁₄ and NR₁₅R₁₆; wherein

R₁₄ is chosen from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

R₁₅ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R₁₆ is chosen from optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl;

or R₁₅ and R₁₆ may optionally be joined together with any interveningatoms to form an optionally substituted heterocycloalkyl ring;

W₁ is chosen from the following moieties:

wherein Y is chosen from O and NR₁₈;

R₁₇ is chosen from cyano, halo, hydroxy, azido, nitro, carboxy,sulfinyl, sulfanyl, optionally substituted alkoxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, optionallysubstituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryloxy, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocycloalkyl, optionallysubstituted amino, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted aminocarbonyl, optionallysubstituted aminosulfonyl, optionally substituted carbaminodoyl, andoptionally substituted alkynyl;

R₁₈ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl;

W₂ is chosen from hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkenyl, and optionallysubstituted alkynyl;

m is selected from 0, 1, 2, and 3;

n is selected from 0 and 1, and

the dotted line represents a single bond or a double bond;

provided that when R₄ is OH, R₁₃ is methyl, W₁ is

(2-oxo-2H-pyran-5-yl), and R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, andW₂ are hydrogen then R₁₂ is not hydrogen.

In some embodiments, R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁, areindependently chosen from hydrogen, hydroxy, optionally substitutedalkyl, optionally substituted alkoxy, optionally substitutedaminocarbonyloxy, optionally substituted acyloxy, optionally substitutedalkoxycarbonyloxy, and optionally substituted amino. In someembodiments, R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ are independentlychosen from hydrogen, hydroxy, and optionally substituted alkyl. In someembodiments, R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ are independentlychosen from hydrogen, hydroxy, and lower alkyl. In some embodiments, R₁,R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ are independently chosen fromhydrogen, hydroxy, and methyl. In some embodiments, R₁, R₂, R₅, R₆, R₉,R₁₀, R₁₁ and R₁₂ are independently chosen from hydrogen, hydroxy, andmethyl; R₃ is chosen from hydroxyl and hydrogen. In some embodiments, atleast one of R₁ and R₂, or R₅ and R₆, or R₇ and R₈, or R₉ and R₁₀, orR₁₁ and R₁₂ mutually independently, together in each case denotes an oxogroup (═O).

In some embodiments, R₄ is hydroxy.

In some embodiments, R₄ and R₅ are joined together with any interveningatoms to form an optionally substituted 3- to 8-memberedheterocycloalkyl ring. In some embodiments, R₄ and R₅ are joinedtogether with any intervening atoms to form an oxirane ring.

In some embodiments, R₇ is chosen from hydrogen, hydroxy, optionallysubstituted alkoxy, optionally substituted aminocarbonyloxy, optionallysubstituted acyloxy, optionally substituted alkoxycarbonyloxy, andoptionally substituted amino. In some embodiments, R₇ is chosen fromhydrogen and optionally substituted acyloxy. In some embodiments, R₇ ischosen from hydrogen and acyloxy. In some embodiments, R₇ is chosen fromhydrogen and —OCOCH₃.

In some embodiments, R₈ and W₂ are independently chosen from hydrogenand optionally substituted alkyl. In some embodiments, R₈ and W₂ areindependently chosen from hydrogen and lower alkyl. In some embodiments,R₈ is hydrogen. In some embodiments, W₂ is hydrogen.

In some embodiments, R₁₃ is chosen from hydrogen and optionallysubstituted alkyl. In some embodiments, R₁₃ is chosen from hydrogen andloweralkyl. In some embodiments, R₁₃ is chosen from hydrogen, methyl,and hydroxymethyl.

In some embodiments, Y is chosen from O, NH and NCH₃. In someembodiments, Y is O.

At least one chemical entity of any one of claims 1 to 15 wherein R₁₇ ischosen from cyano, halo, hydroxy, carboxy, sulfonyl, optionallysubstituted alkoxy, optionally substituted alkoxycarbonyl, optionallysubstituted alkyl, optionally substituted amino, optionally substitutedacyl, optionally substituted alkoxycarbonyl, optionally substitutedaminocarbonyl, and optionally substituted aminosulfonyl.

In some embodiments, m is 0.

In some embodiments, the dotted line represents a single bond.

In some embodiments, the dotted line represents a double bond.

In some embodiments, Z is OR₁₄.

In some embodiments, R₁₄ is chosen from optionally substituted alkyl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl. In some embodiments, R₁₄ is optionally substitutedlower alkyl. In some embodiments, R₁₄ is chosen from 2-morpholinoethyl,2-(pyrrolidin-1-yl)ethyl, and 2-(3-oxopiperazin-1-yl)ethyl.

In some embodiments, Z is NR₁₅R₁₆.

In some embodiments, R₁₅ is chosen from hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl, and R₁₆ is chosen from optionally substituted alkyl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl.

In some embodiments, R₁₅ is hydrogen and R₁₆ is chosen from optionallysubstituted alkyl. In some embodiments, R₁₅ is hydrogen and R₁₆ ischosen from lower alkyl optionally substituted with carboxyl orheterocycloalkyl optionally substituted with one or two groupsindependently chosen from lower alkyl, hydroxyl, and oxo. In someembodiments, R₁₅ is hydrogen and R₁₆ is chosen from 3-carboxypropyl,2-(pyrrolidin-1-yl)ethyl, 2-morpholinoethyl,(4-methylpiperazin-1-yl)ethyl, 2-(4-methyl-2-oxopiperazin-1-yl)ethyl,2-(3-oxopiperazin-1-yl)ethyl, 2-((S)-3-hydroxypyrrolidin-1-yl)ethyl,(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl, 2-(2-oxopiperazin-1-yl)ethyl.

In some embodiments, R₁₅ is hydrogen and R₁₆ is chosen from lower alkyl.

In some embodiments, R₁₅ and R₁₆ are joined together to form anoptionally substituted 4- to 8-membered heterocycloalkyl ring. In someembodiments, R₁₅ and R₁₆ are joined together to form a 4- to 8-memberedheterocycloalkyl ring optionally substituted with one or two groupsindependently chosen from amino, hydroxyl, oxo, and lower alkyl. In someembodiments, R₁₅ and R₁₆ are joined together to form a 5- to 7-memberedheterocycloalkyl ring chosen from 3-hydroxypyrrolidine-1-yl,3-aminopyrrolidine-1-yl, 3-oxopiperazine-1-yl,4-methyl-1,4-diazepane-1-yl, 1,4-diazepane-1-yl, piperazine-1-yl,4-methyl piperazine-1-yl, and morpholine-4-yl.

Also provided is at least one chemical entity chosen from compounds ofFormula Ia

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula Ib

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula Ic

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula Id

Also provided is at least one chemical entity chosen from compounds ofFormula Ie

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula If

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula Ig

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula Ih

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from compounds ofFormula Ii

and pharmaceutically acceptable salts thereof, wherein Z is as definedfor Formula I.

Also provided is at least one chemical entity chosen from the compoundsset forth in Table 1 below and pharmaceutically acceptable saltsthereof.

TABLE 1(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-(pyrrolidin-1-yl)ethyl) carbonate(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-morpholinoethyl) carbonate(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-(pyrrolidin-1-yl) ethyl)carbamate(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-morpholinoethyl)carbamate(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl4-methylpiperazine-1-carboxylate(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11^(a)-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-(4-methylpiperazin-1-yl) ethyl)carbamate(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-ylmorpholine-4-carboxylate4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoicacid(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl4-methylpiperazine-1-carboxylate(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-ylmorpholine-4-carboxylate4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoic aci(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl4-methylpiperazine-1-carboxylate(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-ylmorpholine-4- carboxylate4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoic acid(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1- carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate(S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1- carboxylate(R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1- carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl) carbonate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl)carbonate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl)ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl morpholine-4-carboxylate4-(((((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate(S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate(R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate(S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-aminopyrrolidine-1-carboxylate(R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-aminopyrrolidine-1-carboxylate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl)ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2-oxopiperazin-1-yl) ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-exopiperazin-1-yl)ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3-hydroxypyrrolidin-1-yl) ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3-hydroxypyrrolidin-1-yl) ethyl)carbamate(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl) carbonate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- (pyrrolidin-1-yl)ethyl) carbonate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- morpholinoethyl) carbonate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- (pyrrolidin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- morpholinoethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- (piperazin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate4-(((((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl4- methylpiperazine-1-carboxylate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4- diazepane-1-carboxylate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl4- methyl-1,4-diazepane-1-carboxylate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3- oxopiperazine-1-carboxylate(S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3- hydroxypyrrolidine-1-carboxylate(R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3- hydroxypyrrolidine-1-carboxylate(S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3- aminopyrrolidine-1-carboxylate(R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3- aminopyrrolidine-1-carboxylate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2- oxopiperazin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4- methyl-2-oxopiperazin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3- oxopiperazin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- ((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2- ((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3- oxopiperazin-1-yl)ethyl) carbonate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl) carbonate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl)carbonate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl morpholine-4-carboxylate4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate(S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1- carboxylate(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1- carboxylate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2-oxopiperazin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3-hydroxypyrrolidin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3-hydroxypyrrolidin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl) carbonate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl) ethyl) carbonate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl) carbonate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl (2-morpholinoethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1- carboxylate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4- carboxylate4-(((((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1- carboxylate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1- carboxylate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane- 1-carboxylate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1- carboxylate(S)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1- carboxylate(R)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1- carboxylate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2- oxopiperazin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl) ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3- hydroxypyrrolidin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3- hydroxypyrrolidin-1-yl)ethyl)carbamate(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl) ethyl) carbonate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1- carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(piperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4- carboxylate4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoic acid(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1- carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1- carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-,acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane- 1-carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1- carboxylate(S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 3-hydroxypyrrolidine-1-carboxylate(R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 3-hydroxypyrrolidine-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-yl acetate

The chemical entities described herein can be synthesized utilizingtechniques well known in the art from commercially available startingmaterials and reagents. For example, the chemical entities describedherein can be prepared as illustrated below with reference to theexamples and reaction schemes.

Generally, compounds of Formula I can be prepared through activatedesters such as p-nitrophenylcarbonate as shown in Scheme I. The desiredproduct can be purified from the reaction mixture by standard methods,e.g. by extraction and/or silica gel chromatography or high-pressureliquid chromatography.

The chemical entities described herein may be prepared in substantiallypure form, typically by standard chromatographic methods, prior toformulation in a pharmaceutically acceptable form.

The chemical entities described herein may be used in treating a varietyof cancers. Cancers that can be prevented and/or treated by the chemicalentities, compositions, and methods described herein include, but arenot limited to, human sarcomas and carcinomas, e.g. carcinomas, e.g.,colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer,prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma,lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma,Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cellcarcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,sebaceous gland carcinoma, papillary carcinoma, papillaryadenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma,choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervicalcancer, testicular tumor, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemias, e.g., acutelymphocytic leukemia and acute myelocytic leukemia (myeloblastic,promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronicleukemia (chronic myelocytic (granulocytic) leukemia and chroniclymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin'sdisease and non-Hodgkin's disease), multiple myeloma, Waldenstrom'smacroglobulinemia, and heavy chain disease.

In some embodiments, the chemical entities described herein are used forthe treatment of cancers of the

(i) digestive system including, without limitation, the esophagus,stomach, small intestine, colon (including colorectal), liver &intrahepatic bile duct, gallbladder & other biliary, pancreas, and otherdigestive organs;

(ii) respiratory system, including without limitation, larynx, lung &bronchus, and other respiratory organs;

(iii) breast;

(iv) genital system, including without limitation, uterine cervix,ovary, and prostate;

(v) urinary system, including without limitation, urinary bladder andkidney and renal pelvis; and

(vi) oral cavity & pharynx, including without limitation, tongue, mouth,pharynx, and other oral cavity.

In some embodiments, the chemical entities described herein are used forthe treatment of colorectal cancer, liver cancer, lung cancer, breastcancer and oral cancer.

Chemical entities described herein having the desired pharmacologicalactivity may be administered, in some embodiments, as a pharmaceuticallyacceptable composition comprising an pharmaceutical excipient, to apatient, as described herein. Depending upon the manner of introduction,the chemical entities may be formulated in a variety of ways asdiscussed below. The concentration of the at least one chemical entityin the formulation may vary from about 0.01-100 wt. %.

The administration of the chemical entities described herein can be donein a variety of ways, including, but not limited to, orally,subcutaneously, intravenously, intranasally, transdermally,intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally,or intraocularly.

Pharmaceutical dosage forms include at least one chemical entitydescribed herein and one or more pharmaceutical excipients. As is knownin the art, pharmaceutical excipients are secondary ingredients whichfunction to enable or enhance the delivery of a drug or medicine in avariety of dosage forms (e.g.: oral forms such as tablets, capsules, andliquids; topical forms such as dermal, opthalmic, and otic forms;suppositories; injectables; respiratory forms and the like).Pharmaceutical excipients include inert or inactive ingredients,synergists or chemicals that substantively contribute to the medicinaleffects of the active ingredient. For example, pharmaceutical excipientsmay function to improve flow characteristics, product uniformity,stability, taste, or appearance, to ease handling and administration ofdose, for convenience of use, or to control bioavailability. Whilepharmaceutical excipients are commonly described as being inert orinactive, it is appreciated in the art that there is a relationshipbetween the properties of the pharmaceutical excipients and the dosageforms containing them.

Pharmaceutical excipients suitable for use as carriers or diluents arewell known in the art, and may be used in a variety of formulations.See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. R.Gennaro, Editor, Mack Publishing Company (1990); Remington: The Scienceand Practice of Pharmacy, 21^(st) Edition, Lippincott Williams & Wilkins(2005); Handbook of Pharmaceutical Excipients, 3rd Edition, A. H. Kibbe,Editor, American Pharmaceutical Association, and Pharmaceutical Press(2000); and Handbook of Pharmaceutical Additives, compiled by Michaeland Irene Ash, Gower (1995), each of which is incorporated herein byreference for all purposes.

Oral solid dosage forms such as tablets will typically comprise one ormore pharmaceutical excipients, which may for example help impartsatisfactory processing and compression characteristics, or provideadditional desirable physical characteristics to the tablet. Suchpharmaceutical excipients may be selected from diluents, binders,glidants, lubricants, disintegrants, colors, flavors, sweetening agents,polymers, waxes or other solubility-retarding materials.

Compositions for intravenous administration will generally compriseintravenous fluids, i.e., sterile solutions of simple chemicals such assugars, amino acids or electrolytes, which can be easily carried by thecirculatory system and assimilated.

Dosage forms for parenteral administration will generally comprisefluids, particularly intravenous fluids, i.e., sterile solutions ofsimple chemicals such as sugars, amino acids or electrolytes, which canbe easily carried by the circulatory system and assimilated. Such fluidsare typically prepared with water for injection USP. Fluids usedcommonly for intravenous (IV) use are disclosed in Remington: TheScience and Practice of Pharmacy, Lippincott Williams & Wilkins (2005).The pH of such IV fluids may vary, and will typically be from 3.5 to 8as known in the art.

The chemical entities described herein may also be used in conjunctionwith other well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the chemical entities described herein may be useful incombination with at least one additional anti-cancer and/or cytotoxicagents. Further, the chemical entities described herein may also beuseful in combination with other inhibitors of parts of the signalingpathway that links cell surface growth factor receptors to nuclearsignals initiating cellular proliferation.

Such known anti-cancer and/or cytotoxic agents that may be used incombination with the chemical entities described herein include:

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and anti folatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumorantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycinC,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5a-reductase suchas finasteride;

(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 66586661) and bosutinib(SK1-606), and metalloproteinase inhibitors like marimastat, inhibitorsof urokinase plasminogen activator receptor function or antibodies toHeparanase];

(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifamib (RI15777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, P13 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR kinaseinhibitors, IGF receptor (insulin like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compoundssuch as those disclosed in International Patent Applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds thatwork by other mechanisms (for example linomide, inhibitors of integrinav˜3 function and angiostatin));

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;

(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase subject tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of subject's tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies.

In certain embodiments, the at least one chemical entity administered incombination with one or more agents chosen from pacliataxel, bortezomib,dacarbazine, gemcitabine, trastuzumab, bevacizumab, capecitabine,docetaxel, erlotinib, aromatase inhibitors, such as AROMASIN™(exemestane), and estrogen receptor inhibitors, such as FASLODEX™(fulvestrant).

When a chemical entity described herein is administered into a humansubject, the daily dosage will normally be deter mined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual subject, as well as theseverity of the subject's symptoms.

In one exemplary application, a suitable amount of at least one chemicalentity is administered to a mammal undergoing treatment for cancer, forexample, breast cancer. Administration typically occurs in an amount ofbetween about 0.01 mg/kg of body weight to about 100 mg/kg of bodyweight per day (administered in single or divided doses), such as atleast about 0.1 mg/kg of body weight per day. A particular therapeuticdosage can include, e.g., from about 0.01 mg to about 1000 mg of thechemical entity, such as including, e.g., from about 1 mg to about 1000mg. The quantity of the at least one chemical entity in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg, suchas from about 1 mg to 300 mg, for example 10 mg to 200 mg, according tothe particular application. The amount administered will vary dependingon the particular IC₅₀ value of the at least one chemical entity usedand the judgment of the attending clinician taking into considerationfactors such as health, weight, and age. In combinational applicationsin which the at least one chemical entity described herein is not thesole active ingredient, it may be possible to administer lesser amountsof the at least one chemical entity and still have therapeutic orprophylactic effect.

In some embodiments, the pharmaceutical preparation is in unit dosageform. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the subject and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the at least onechemical entity. Thereafter, the dosage is increased by small amountsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The amount and frequency of administration of the at least one chemicalentities described herein, and if applicable other chemotherapeuticagents and/or radiation therapy, will be regulated according to thejudgment of the attending clinician (physician) considering such factorsas age, condition and size of the subject as well as severity of thedisease being treated.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thesubject, and in view of the observed responses of the disease to theadministered therapeutic agents.

Also, in general, the at least one chemical entities described hereinneed not be administered in the same pharmaceutical composition as achemotherapeutic agent, and may, because of different physical andchemical characteristics, be administered by a different route. Forexample, the chemical entities/compositions may be administered orallyto generate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of chemical entity (and where appropriate,chemotherapeutic agent and/or radiation) will depend upon the diagnosisof the attending physicians and their judgment of the condition of thesubject and the appropriate treatment protocol.

The chemical entities described herein (and where appropriatechemotherapeutic agent and/or radiation) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, depending upon the natureof the proliferative disease, the condition of the subject, and theactual choice of chemotherapeutic agent and/or radiation to beadministered in conjunction (i.e., within a single treatment protocol)with the chemical entity/composition.

In combinational applications and uses, the chemical entity/compositionand the chemotherapeutic agent and/or radiation need not be administeredsimultaneously or essentially simultaneously, and the initial order ofadministration of the chemical entity/composition, and thechemotherapeutic agent and/or radiation, may not be important. Thus, theat least one chemical entity described herein may be administered firstfollowed by the administration of the chemotherapeutic agent and/orradiation; or the chemotherapeutic agent and/or radiation may beadministered first followed by the administration of the at least onechemical entity described herein. This alternate administration may berepeated during a single treatment protocol. The determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is well withinthe knowledge of the skilled physician after evaluation of the diseasebeing treated and the condition of the subject. For example, thechemotherapeutic agent and/or radiation may be administered first, andthen the treatment continued with the administration of the at least onechemical entity described herein followed, where determinedadvantageous, by the administration of the chemotherapeutic agent and/orradiation, and so on until the treatment protocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a chemicalentity/composition for treatment according to the individual subject'sneeds, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thesubject as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radiological studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe invention. These examples are presented for illustrative purposesand should not serve to limit the true scope of the invention.

In carrying out the procedures of the methods described herein, it is ofcourse to be understood that reference to particular buffers, media,reagents, cells, culture conditions and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

Example I Preparation of(3S,5R,8R,9S,10R,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-5,10,13-trimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate

To a solution of(3S,5R,8R,9S,10S,13R,14S,16S,17R)-3,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate (200 mg, 0.45 mmol) and DMAP (55 mg, 0.45 mmol) in CHCl₃ (30 mL)were added DIEA (230 mg, 4 mmol) and 4-nitrophenyl carbonochloridate(360 mg, 4 mmol). The mixture was stirred at 65° C. for 16 h. Themixture was evaporated and the residue was purified via preparative TLC(PE/EA=2:1) to afford(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((4-nitrophenoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate as a white solid (230 mg, 84%).

To a solution of(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((4-nitrophenoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate (100 mg, 0.16 mmol) in CH₂Cl₂ was added piperazine (141 mg, 1.6mmol). The mixture was stirred at room temperature for 16 h. The mixturewas concentrated and the resulting residue was purified via preparativeTLC (CH₂Cl₂/MeOH=5:1) to afford(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate (40 mg, 44%) as a white solid. LRMS (M+H⁺) m/z557.3. ¹H NMR (CD₃OD, 400 MHz) δ 8.13-8.16 (dd, 1H), 7.33 (m, 1H),6.10-6.12 (d, 1H), 5.39-5.43 (m, 1H), 4.91 (s, 1H), 3.52 (s, 4H),2.94-2.97 (m, 4H), 2.86-2.88 (d, 1H), 2.58-2.64 (m, 1H), 1.11-1.95 (m,23H), 0.89 (s, 3H), 0.68 (s, 3H).

Example II Preparation of(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate

To a solution of4-((3S,5R,8R,9S,10S,13R,14S,17R)-3,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)furan-2(5H)-one(17.21 mg, 0.046 mmol) and DMAP (5.6 mg, 0.046 mmol) in CHCl₃ (5 mL)were added DIEA (23.87 mg, 0.185 mmol) and 4-nitrophenylcarbonochloridate (37.2 mg, 0.185 mmol). The mixture was stirred at 70°C. for 16 h. The solvent was evaporated and the resulting residue waspurified via preparative TLC (PE/EA=2:1) to give the crude(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-nitrobenzoate.

To a solution of crude(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-nitrobenzoate (5 mg) in CH₂Cl₂ was added piperazine (4 mg, 0.045mmol). The mixture was stirred at room temperature for 16 h. The mixturewas concentrated and the resulting residue was purified via Prep-HPLC toafford(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate (1.1 mg). LRMS (M+H⁺) m/z 487.3. ¹H NMR (CDCl₃,400 MHz) δ 5.88 (s, 1H), 5.32 (m, 1H), 4.97-5.05 (m, 3H), 4.78-4.83 (m,1H), 3.83 (s, 4H), 3.19-3.20 (m, 4H), 2.81 m, 1H), 1.90-2.03 (m, 3H),1.60-1.89 (m, 14H), 1.28-1.57 (m, 31H), 0.86-0.96 (m, 12H).

Example III Inhibition of Cell Growth in Tumor Cells

Inhibition of cell growth by compounds was measured using MTT assay(Mosmann, T., Journal of Immunological Methods, 1983, 65, 55-63). Tumorcell lines were purchased from ATCC (American Type Culture Collection,Manassas, Va.). All cell lines were maintained in RPMI 1640 (Hyclone)supplemented with 10% fetal bovine serum (FBS, Hyclone), glutamine (2mM, Hyclone), and antibiotics (penicillin 100 U/mL and streptomycin 50μg/mL) at 37° C. in a humidified atmosphere of 5% CO₂ in air. Taxol(positive control, Sigma) and compounds were dissolved in DMSO (Sigma),and the final concentration of DMSO in the medium was 1%. Tumor cellswere plated in 96-well plates at densities from 4000 cells/well of a96-well plate and allowed to adhere/grow for 24 h. They were thentreated with various concentrations of drug for 72 h.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT,Sigma) was used to determine the number of viable cells at the time ofcompound addition and the number of cells remaining after 72 h compoundexposure. The number of cells remaining after 72 h was compared to thenumber of viable cells at the time of compound addition by measuring theabsorbance at 570 nm, allowing for the calculation of growth inhibition.

All concentrations of compounds were tested in triplicate and controlswere averaged over 4 wells. IC₅₀ was calculated by plotting theconcentration of compound vs the percentage of inhibition in treatedwells using GraphPad Prism 5. Each of the compounds described in Table Iabove exhibit an IC₅₀ for A549 cells of less than 100 μM. In someembodiments, the compounds exhibit an IC₅₀ for A549 cells of less than10 μM. In some embodiments, the compounds exhibit an IC₅₀ for A549 cellsof less than 1 μM. In some embodiments, the compounds exhibit an IC₅₀for A549 cells of less than 100 nM. Data for representative compoundsare shown below.

TABLE 2 Inhibitory activity of representative compounds in A549 cells.A549 cell Chemical Name IC₅₀ (nM)(3S,5R,8R,9S,10R,13R,14S,16S,17R)-16-acetoxy-14- 5.6hydroxy-5,10,13-trimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren- 3-ylpiperazine-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl- 3917-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl piperazine-1-carboxylate

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1. At least one chemical entity chosen from compounds of Formula I

and pharmaceutically acceptable salts thereof, wherein R₁, R₂, R₃, R₅,R₆, R₉, R₁₀, R₁₁ and R₁₂ are independently chosen from hydrogen,hydroxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substitutedheterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionallysubstituted acyloxy, optionally substituted alkoxycarbonyloxy, andoptionally substituted amino; or R₁ and R₂, or R₅ and R₆, or R₇ and R₈,or R₉ and R₁₀, or R₁₁ and R₁₂ mutually independently, together in eachcase denote an oxo group (═O); R₄ is hydroxy, or R₄ and R₅ mayoptionally be joined together with any intervening atoms to form anoptionally substituted heterocycloalkyl ring; R₇ is chosen fromhydrogen, hydroxy, optionally substituted alkoxy, optionally substitutedaryloxy, optionally substituted heteroaryloxy, optionally substitutedheterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionallysubstituted acyloxy, optionally substituted alkoxycarbonyloxy, andoptionally substituted amino; R₈ is chosen from hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkenyl, and optionally substituted alkynyl; R₁₃ is chosenfrom hydrogen, optionally substituted alkyl, and formyl; Z is chosenfrom OR₁₄ and NR₁₅R₁₆; wherein R₁₄ is chosen from optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; R₁₅ is chosen from hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; R₁₆ is chosen from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, andoptionally substituted heteroaryl; or R₁₅ and R₁₆ may optionally bejoined together with any intervening atoms to form an optionallysubstituted heterocycloalkyl ring; W₁ is chosen from the followingmoieties:

wherein Y is chosen from O and NR₁₈; R₁₇ is chosen from cyano, halo,hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionallysubstituted alkoxy, optionally substituted aryloxy, optionallysubstituted heteroaryloxy, optionally substituted heterocycloalkyloxy,optionally substituted alkoxycarbonyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted aryloxy,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycloalkyl, optionally substituted amino,optionally substituted acyl, optionally substituted alkoxycarbonyl,optionally substituted aminocarbonyl, optionally substitutedaminosulfonyl, optionally substituted carbaminodoyl, and optionallysubstituted alkynyl; R₁₈ is chosen from hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; W₂ is chosen from hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkenyl, and optionally substituted alkynyl; m is selectedfrom 0, 1, 2, and 3; n is selected from 0 and 1, and the dotted linerepresents a single bond or a double bond; provided that when R₄ is OH,R₁₃ is methyl, W₁ is

(2-oxo-2H-pyran-5-yl), and R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, andW₂ are hydrogen then R₁₂ is not hydrogen.
 2. At least one chemicalentity of claim 1 wherein R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ areindependently chosen from hydrogen, hydroxy, optionally substitutedalkyl, optionally substituted alkoxy, optionally substitutedaminocarbonyloxy, optionally substituted acyloxy, optionally substitutedalkoxycarbonyloxy, and optionally substituted amino.
 3. At least onechemical entity of claim 2 wherein R₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ andR₁₂ are independently chosen from hydrogen, hydroxy, and optionallysubstituted alkyl.
 4. At least one chemical entity of claim 3 whereinR₁, R₂, R₃, R₅, R₆, R₉, R₁₀, R₁₁ and R₁₂ are independently chosen fromhydrogen, hydroxy, and methyl.
 5. At least one chemical entity of claim1 wherein R₄ is hydroxy.
 6. At least one chemical entity of claim 1wherein R₄ and R₅ are joined together with any intervening atoms to forman optionally substituted 3- to 8-membered heterocycloalkyl ring.
 7. Atleast one chemical entity of claim 6 wherein R₄ and R₅ are joinedtogether with any intervening atoms to form an oxirane ring.
 8. At leastone chemical entity of claim 1 wherein R₇ is chosen from hydrogen,hydroxy, optionally substituted alkoxy, optionally substitutedaminocarbonyloxy, optionally substituted acyloxy, optionally substitutedalkoxycarbonyloxy, and optionally substituted amino.
 9. At least onechemical entity of claim 8 wherein R₇ is chosen from hydrogen andoptionally substituted acyloxy.
 10. At least one chemical entity ofclaim 9 wherein R₇ is chosen from hydrogen and —OCOCH₃.
 11. At least onechemical entity of claim 1 wherein R₈ and W₂ are independently chosenfrom hydrogen and optionally substituted alkyl.
 12. At least onechemical entity of claim 1 wherein R₁₃ is chosen from hydrogen andoptionally substituted alkyl.
 13. At least one chemical entity of claim12 wherein R₁₃ is chosen from hydrogen, methyl, and hydroxymethyl. 14.At least one chemical entity of claim 1 wherein Y is chosen from O, NHand NCH₃.
 15. At least one chemical entity of claim 14 wherein Y is O.16. At least one chemical entity of claim 1 wherein R₁₇ is chosen fromcyano, halo, hydroxy, carboxy, sulfonyl, optionally substituted alkoxy,optionally substituted alkoxycarbonyl, optionally substituted alkyl,optionally substituted amino, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted aminocarbonyl, andoptionally substituted aminosulfonyl.
 17. At least one chemical entityof claim 1 wherein m is
 0. 18. At least one chemical entity of claim 1wherein the dotted line represents a single bond.
 19. At least onechemical entity of claim 1 wherein the dotted line represents a doublebond.
 20. At least one chemical entity of claim 1 wherein the compoundof Formula I is chosen from compounds of Formula Ia.


21. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Ib.


22. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Ic.


23. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Id.


24. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Ie.


25. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula If.


26. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Ig.


27. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Ih.


28. At least one chemical entity of claim 1 wherein the compound ofFormula I is chosen from compounds of Formula Ii.


29. At least one chemical entity of claim 1, wherein Z is OR₁₄.
 30. Atleast one chemical entity of claim 29 wherein R₁₄ is chosen fromoptionally substituted alkyl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl.
 31. At least one chemicalentity of claim 30 wherein R₁₄ is optionally substituted lower alkyl.32. At least one chemical entity of claim 31 wherein R₁₄ is chosen from2-morpholinoethyl, 2-(pyrrolidin-1-yl)ethyl, and2-(3-oxopiperazin-1-yl)ethyl.
 33. At least one chemical entity of claim1, wherein Z is NR₁₅R₁₆.
 34. At least one chemical entity of claim 33wherein R₁₅ is chosen from hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl, and R₁₆ is chosen from optionally substituted alkyl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl.
 35. At least one chemical entity of claim 34 whereinR₁₅ is hydrogen and R₁₆ is chosen from optionally substituted alkyl. 36.At least one chemical entity of claim 35 wherein R₁₅ is hydrogen and R₁₆is chosen from lower alkyl optionally substituted with carboxyl orheterocycloalkyl optionally substituted with one or two groupsindependently chosen from lower alkyl, hydroxyl, and oxo.
 37. At leastone chemical entity of claim 36 wherein R₁₅ is hydrogen and R₁₆ ischosen from 3-carboxypropyl, 2-(pyrrolidin-1-yl)ethyl,2-morpholinoethyl, (4-methylpiperazin-1-yl)ethyl,2-(4-methyl-2-oxopiperazin-1-yl)ethyl, 2-(3-oxopiperazin-1-yl)ethyl,2-((S)-3-hydroxypyrrolidin-1-yl)ethyl,(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl, and2-(2-oxopiperazin-1-yl)ethyl.
 38. At least one chemical entity of claim33 wherein R₁₅ and R₁₆ are joined together to form an optionallysubstituted 4- to 8-membered heterocycloalkyl ring.
 39. At least onechemical entity of claim 38 wherein R₁₅ and R₁₆ are joined together toform a 4- to 8-membered heterocycloalkyl ring optionally substitutedwith one or two groups independently chosen from amino, hydroxyl, oxo,and lower alkyl.
 40. At least one chemical entity of claim 39 whereinR₁₅ and R₁₆ are joined together to form a 5- to 7-memberedheterocycloalkyl ring chosen from 3-hydroxypyrrolidine-1-yl,3-aminopyrrolidine-1-yl, 3-oxopiperazine-1-yl,4-methyl-1,4-diazepane-1-yl, 1,4-diazepane-1-yl, piperazine-1-yl,4-methylpiperazine-1-yl, and morpholine-4-yl.
 41. At least one chemicalentity chosen from(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-(pyrrolidin-1-yl)ethyl) carbonate,(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-morpholinoethyl) carbonate,(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-(pyrrolidin-1-yl)ethyl)carbamate,(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-morpholinoethyl)carbamate,(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl4-methylpiperazine-1-carboxylate,(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11^(a)-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl(2-(4-methylpiperazin-1-yl)ethyl)carbamate,(1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-ylmorpholine-4-carboxylate,4-(((((1R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoicacid,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-yl acetate,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl4-methylpiperazine-1-carboxylate,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-ylmorpholine-4-carboxylate,4-(((((1R,2R,2aR,3aS,3bR,5aR,7S,9aS,9bS,11aR)-2-acetoxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoicacid,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethoxy)carbonyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)-7-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-morpholinoethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-2-ylacetate,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl4-methylpiperazine-1-carboxylate,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-5a-hydroxy-9a,11a-dimethyl-7-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno [1,7a-b]oxiren-2-yl acetate,(1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-ylmorpholine-4-carboxylate,4-(((((1R,2R,2aR,3aS,3bR,5aS,7S,9aR,9bS,11aR)-2-acetoxy-5a-hydroxy-9a,11a-dimethyl-1-(2-oxo-2H-pyran-5-yl)hexadecahydronaphtho[1′,2′:6,7]indeno[1,7a-b]oxiren-7-yl)oxy)carbonyl)amino)butanoicacid,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate,4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate,(S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbonate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbonate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate,4-(((((3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate,(S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(S)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-aminopyrrolidine-1-carboxylate,(R)-(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-aminopyrrolidine-1-carboxylate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,5S,8R,9S,10R,13R,14S,17R)-5,14-dihydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbonate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbonate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbonate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate,4-(((((3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate,(S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(S)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3-aminopyrrolidine-1-carboxylate,(R)-(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl3-aminopyrrolidine-1-carboxylate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbonate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbonate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbonate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate,4-(((((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate,(S)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(R)-(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbonate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbonate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbonate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(pyrrolidin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-morpholinoethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(piperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate,4-(((((3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate,(S)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(R)-(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(2-oxopiperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamate,(3S,5R,8R,9S,10S,12R,13S,14S,17R)-12,14-dihydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(2-(3-oxopiperazin-1-yl)ethyl)carbonate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-yl(2-(pyrrolidin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethoxy)carbonyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-morpholinoethyl)carbamoyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(piperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylmorpholine-4-carboxylate,4-(((((3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)amino)butanoicacid,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methylpiperazine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl-1,4-diazepane-1-carboxylate(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-,acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl4-methyl-1,4-diazepane-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-oxopiperazine-1-carboxylate,(S)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(R)-(3S,5R,8R,9S,10S,13R,14S,16S,17R)-16-acetoxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl3-hydroxypyrrolidine-1-carboxylate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-3-(((2-(4-methyl-2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((3-(2-oxopiperazin-1-yl)ethyl)carbamoyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate,(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-3-(((2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)carbamoyl)oxy)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate, and(3S,5R,8R,9S,10S,13R,14S,16S,17R)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-3-(((2-(3-oxopiperazin-1-yl)ethoxy)carbonyl)oxy)hexadecahydro-1H-cyclopenta[a]phenanthren-16-ylacetate, and pharmaceutically acceptable salts thereof.
 42. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and at least one chemical entity of claim
 1. 43. Apharmaceutical composition of claim 42 wherein the composition isformulated in a form chosen from tablets, capsules, powders, liquids,suspensions, suppositories, and aerosols.
 44. A packaged pharmaceuticalcomposition comprising a pharmaceutical composition of claim 42 andinstructions for using the composition to treat a subject suffering fromcancer.
 45. A method of treating cancer in a subject which comprisesadministering to a subject in need thereof a therapeutically effectiveamount of at least one chemical entity of claim 1.